Neurocognitive and Metabolic Effects of Mild Hypothyroidism

轻度甲状腺功能减退症的神经认知和代谢影响

• 批准号: 8100223
• 负责人: MARY H SAMUELS
• 金额: $ 46.78万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-05 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100223
• 关键词: 3-iodothyronamine; Adult; Affect; American; Area; Biological Assay; Body Composition; Brain; Chronic; Cognition; Cognitive; Confusion; Consensus; DEXA; Data; Decarboxylation; Decision Making; Diagnosis; Dose; Double-Blind Method; Energy Metabolism; Epidemiologic Studies; Experimental Designs; Experimental Models; Fatty acid glycerol esters; Food; Functional disorder; Funding; Genetic Transcription; Health; Heart; Hormone replacement therapy; Human; Hypothyroidism; Indirect Calorimetry; Individual; Investigation; Label; Laboratories; Lead; Liver; Measurement; Measures; Mediating; Metabolic; Metabolism; Modeling; Monitor; Moods; National Institute of Diabetes and Digestive and Kidney Diseases; Nervous System Physiology; Neuraxis; Neurocognitive; Normal Range; Organ; Outcome; Outcome Measure; Patients; Physical activity; Population; Public Health; Quality of life; Randomized; Recommendation; Research; Research Design; Research Personnel; Rest; Serum; Short-Term Memory; Skeletal Muscle; Symptoms; Syndrome; System; Techniques; Text; Thyroid Diseases; Thyroid Function Tests; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Time; Titrations; Triiodothyronine; Visit; Water; Work; base; bone; clinically relevant; cognitive function; design; executive function; insight; model design; motor learning; novel; older women; oxidation; population based; psychologic; respiratory

DESCRIPTION (provided by applicant): Hypothyroidism is common, affecting 3% of the U.S. population, and up to 20% of older women. Therapy is straightforward, with optimization of target organ function expected when thyroid stimulating hormone (TSH) levels are normalized using L-thyroxine (L-T4). Despite this, millions of patients have mildly elevated TSH levels, and recent data also imply that patients may be undertreated if their TSH levels are high- normal. Decrements in quality of life, mood, cognitive function, and fuel metabolism are seen in hypothyroidism, but much less is known regarding these outcomes in mild hypothyroidism, or in L-T4 treated subjects with high-normal TSH levels. Preliminary data: The investigator's work utilizes a unique experimental model of experimentally-induced mild thyroid disease in hypothyroid subjects on chronic L-T4 therapy. This NIDDK R21-funded work has resulted in intriguing preliminary data that form the basis for the current R01 application. Experimental design: The current proposal is to extend this model to the mildest forms of hypothyroidism, associated with high-normal or mildly elevated TSH levels. L-T4 treated hypothyroid subjects will be randomized to doses of L-T4 that target three TSH ranges: 0.28 2.49 mU/L (the lower normal range, the theoretical optimal range), 2.5 5.0 mU/L (the upper normal range), or 5.1 12 mU/L (the mild hypothyroid range). Precisely titrated L-T4 doses will be given in a double-blinded, parallel study lasting 6 months, in order to achieve these TSH levels. Outcomes focus on the most clinically relevant and least studied systems: the brain (mood and cognition) and intermediary metabolism (energy expenditure and body composition), for which the investigator has already found effects in previous work. These outcome variables will be measured using validated techniques at baseline and at 6 months, with interim visits to allow precise titration of L-T4 doses. Relevance: This is the first investigation that focuses on neurocognitive and metabolic effects of mild hypothyroidism utilizing a rigorous study design and validated, relevant outcome measures. There is no consensus over whether to treat patients with TSH levels in the ranges proposed in this study, and these TSH ranges are the subject of intense debate within the thyroid field. Therefore, this study has major public health implications for the millions of Americans who receive thyroid hormone replacement therapy, as well as for the additional millions with high-normal serum TSH levels. PUBLIC HEALTH RELEVANCE: Millions of people in the U.S. have mild hypothyroidism or thyroid function in the low-normal range. Recent preliminary studies, including those from the investigator's laboratory, suggest that there are clinically relevant end-organ effects of thyroid function in this range, but there is a dearth of conclusive data, especially in the critical areas of brain function and fuel metabolism. This study will utilize a rigorous interventional design and validated outcome measures to study this for the first time, with results that have the potential to inform treatment decisions for millions of people.

描述（由申请人提供）：甲状腺功能减退症很常见，影响 3% 的美国人口，以及高达 20% 的老年女性。治疗很简单，当使用 L-甲状腺素 (L-T4) 使促甲状腺激素 (TSH) 水平正常化时，预计会优化靶器官功能。尽管如此，数百万患者的 TSH 水平轻度升高，最近的数据还表明，如果患者的 TSH 水平处于正常高值，则可能未得到充分治疗。甲状腺功能减退症患者会出现生活质量、情绪、认知功能和燃料代谢的下降，但对于轻度甲状腺功能减退症或 TSH 水平正常高的 L-T4 治疗受试者的这些结果知之甚少。初步数据：研究者的工作利用了一种独特的实验模型，在接受长期 L-T4 治疗的甲状腺功能减退受试者中实验诱发轻度甲状腺疾病。这项 NIDDK R21 资助的工作产生了有趣的初步数据，构成了当前 R01 申请的基础。实验设计：目前的建议是将这个模型扩展到最轻度的甲状腺功能减退症，与正常高值或轻度升高的 TSH 水平相关。 L-T4 治疗的甲状腺功能减退受试者将随机接受 L-T4 剂量，目标为三个 TSH 范围：0.28-2.49 mU/L（正常范围下限，理论最佳范围）、2.5-5.0 mU/L（正常范围上限）或 5.1-12 mU/L（轻度甲状腺功能减退范围）。为了达到这些 TSH 水平，将在持续 6 个月的双盲、平行研究中给予精确滴定的 L-T4 剂量。结果集中在临床最相关且研究最少的系统：大脑（情绪和认知）和中间代谢（能量消耗和身体成分），研究人员已经在之前的工作中发现了这些系统的影响。这些结果变量将使用经过验证的技术在基线和 6 个月时进行测量，并进行中期访视以精确调整 L-T4 剂量。相关性：这是第一项利用严格的研究设计和经过验证的相关结果测量来关注轻度甲状腺功能减退症对神经认知和代谢影响的研究。对于是否对 TSH 水平在本研究提出的范围内的患者进行治疗尚未达成共识，并且这些 TSH 范围是甲状腺领域内激烈争论的主题。因此，这项研究对于数百万接受甲状腺激素替代疗法的美国人以及数百万血清 TSH 水平正常高的人具有重大的公共卫生意义。公众健康相关性：在美国，数百万人患有轻度甲状腺功能减退症或甲状腺功能处于正常低值范围。最近的初步研究，包括来自研究者实验室的研究，表明在这个范围内甲状腺功能存在临床相关的终末器官效应，但缺乏确凿的数据，特别是在脑功能和燃料代谢的关键领域。这项研究将首次利用严格的干预设计和经过验证的结果测量来研究这一问题，其结果有可能为数百万人的治疗决策提供信息。